Cannabinoids are present in Indian hemp Cannabis sativa and have been well known for their medicinal properties for ages. Cannabinoids as a therapeutic agents is however a recent phenomenon. (Williamson E. M. & Evans E. J. Drugs 2000 December; 60(6): 1303-14) Research in this area over the last decade have provided very important information on the cannabinoid receptors and their agonists and antagonists. Development of central Cannabinoid receptor ligands with lower lipophilicity.(J. Med. Chem. 2003; 46:642-645) Further cloning and isolation of two different subtypes of cannabinoid receptors—CB1 (central subtype) and CB2 (peripheral subtype) and the first endogenous ligand N-arachidonyl ethanolamine amide(AEA); anadamide (Matsuda L A et. al., Nature 1990; 346:561-4; Devane W A et. al. J. Med. Chem. 1992; 35:2065-9; Munro, S. et. al., Nature 1993, 365, 61-5) have stimulated research in this field. There has also been an increased interest among the different pharmaceutical companies in developing drugs for the treatment of diseases connected with disorders of the cannabinoid systems (Greenberg D. A., Drugs News & Perspectives 1999; 12: 458; Kulkarni S. K. & Ninan, Indian Journal of Pharmacology 2001; 33: 170-184; Piomelli D et. al., Trends Pharmacol Sci. 2000 June; 21(6): 218-24). Several compounds which are either CB1 &/or CB2 antagonists have been reported and are under various stages of development for e.g. SR-141716 A(Sanofi), CP-272871 (fizer), LY-320135 (Eli Lily), AM-630 (Alexis), SR-144528 (Sanofi) etc. Novel compounds which are selective CB1 and/or CB2 antagonists, their preparation and their use in medicine have also been reported in U.S. Pat. Nos. 5,925,768, 6,344,474, 6,028,084, 5,462,960, EP 0656354, U.S. Pat. Nos. 6,432,984, 6,509,367 B1, U.S. Pat. No. 5,624,941, EP1230222, EP 122952, FR 2816938, FR 2761266, FR 2800375, EP 0656354, EP 0576357, WO 03027076, WO 03026648, WO 03026647, WO 03020217, WO 0158450, WO 0185092, WO 0132663, WO 0132629 which are incorporated as references in their entirety. Synthesis and biological evaluation of novel 4,5-dihydro-1H-benzo [g] indazole- based ligands for cannabinoid receptors has been described in Bioorg. Med. Chem., 2005, 13, 3309-3320.
Synthesis of tricyclic pyrazole derivative (NESS 0327) as CB1 antagonist has been disclosed in J. Pharmacology & Experimental Therapeutics, 2003, 306(1), 363-370. Synthesis and activity of tricyclic pyrazole ligands for CB1 & CB2 receptors have been disclosed in Bioorg. Med. Chem., 2003, 11, 251-263.
Structure elucidation of novel ring constrained biaryl pyrazole CB1 cannabinoid receptor antagonist has been described in Magn. Reson. Chem. 2003, 41, 265-268.
Synthesis and biological activity of rigid cannabinoid CB1 cannabinoid receptor antagonists has been disclosed in Chem. Pharm. Bull. 2002, 50, 1109-1113.
Tricyclic benzopyrazole derivatives as cyclooxygenase-2 (COX-2) inhibitors have been disclosed in WO 9609304, which is also incorporated herein as reference.
Though research in the area of cannabinoids have been going on for more than a decade there are only few medicines available which modulate the cannabinoid receptors and fewer with minor side effects. Looking at the beneficial effects of cannabinoids, it would be highly desired to develop compounds, which modulate the cannabinoid receptors, having better or comparable absorption, metabolic stability, and exhibiting lesser toxicity.